Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
  • C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to a novel indole-containing peptide having an antihypertensive activity and/or heart failure curing activity and a process for preparing the same.
• Atrial natriuretic peptide secreted from atrial myocytes has strong diuretic, natriuretic and vasodilating activities and inhibitory activity on renin-angiotensin-aldosterone system, and that ANP is effective for curing hypertension and heart failure.
• ANP itself is a polypeptide and poorly absorbed in the digestive tracts, so that its administration route is limited to parenteral route.
• ANP is inactivated by neutral metalloendopeptidase, and that the inhibitor of the enzyme can be used as a medicine for curing hypertension and/or heart failure because it increases a concentration of ANP in the blood.
• An object of the present invention is to provide an indole-containing peptide having excellent neutral metalloendopeptidase inhibitory activity and being useful as an antihypertensive drug and/or a medicine for curing heart failure.
• the present invention relates to an indole-containing peptide represented by the formula (I): wherein R represents hydrogen atom, a lower alkyl group or formyl group; and X represents oxygen atom or sulfur atom, an ester thereof or pharmaceutically acceptable salts thereof, and also relates to a process for preparing the same.
• a free carboxylic acid-type compound has excellent pharmaceutical activity, and an ester thereof is a prodrug which is hydrolyzed to be a free carboxylic acid-type compound exhibiting the activity through metabolism in vivo .
• R is hydrogen atom, methyl group or formyl group.
• R is hydrogen atom
• X is oxygen atom.
• Other preferred examples of the desired compound (I) are those represented by the formula (I-a): wherein the symbols have the same meaning as bove.
• ester residue there may be used any one which does not influence pharmaceutical effects of a free carboxylic acid-type compound when hydrolyzed in vivo , and is pharmaceutically acceptable.
• an ester residue may include an ester residue such as a lower alkyl ester, a halogen-substituted lower alkyl ester, a phenyl-lower alkyl ester or a phenacyl ester.
• the ester compound there may be mentioned, for example, mono lower alkyl ester, di lower alkyl ester, mono(phenyl lower alkyl) ester, di(phenyl lower alkyl) ester and mono lower alkyl-mono(phenyl lower alkyl) ester.
• a preferred ester compound is a mono or di lower alkyl ester compound, and particularly preferred is a mono- or diethyl ester compound.
• a pharmaceutically acceptable salt of the desired compound (I) of the present invention or an ester thereof there may be mentioned, for example, an inorganic acid addition salt such as hydrobromide, hydrochloride, sulfate, phosphate and nitrate; an organic acid addition salt such as methanesulfonate, p-toluenesulfonate, oxalate, fumarate, maleate, tartrate and citrate; and an alkali metal salt such as sodium salt and potassium salt.
• an inorganic acid addition salt such as hydrobromide, hydrochloride, sulfate, phosphate and nitrate
• an organic acid addition salt such as methanesulfonate, p-toluenesulfonate, oxalate, fumarate, maleate, tartrate and citrate
• an alkali metal salt such as sodium salt and potassium salt.
• the desired compound (I) of the-present invention includes 4 kinds of optically active isomers based on two asymmetric carbon atoms and a mixture thereof. Among them, those in which both of two asymmetric carbon atoms have S configurations (hereinafter referred to "(S-S) isomer”) are pharmaceutically particularly preferred.
• the lower alkyl group means an alkyl group having 1 to 6 carbon atoms, preferably, an alkyl group having 1 to 4 carbon atoms.
• the desired compound (I), an ester thereof or a salt thereof can be administered orally or parenterally, if necessary, in admixture with conventional pharmaceutically acceptable carrier, diluent or disintegrant suitable for oral or parenteral administration.
• the pharmaceutical preparation may be either a solid preparation such as a tablet, a capsule and a powder or a liquid preparation such as a solution, a suspension and an emulsion. Further, in the case of parenteral administration, it may be also used as an injection.
• the dose varies depending on an administration method, age, body weight and state of a patient and a kind of a disease to be cured, but, in general, it may be preferably about 1 to 100 mg/kg, particularly about 3 to 30 mg/kg per day.
• the desired compound (I) can be prepared by:
• an ester residue such as a lower alkyl ester, a halogen-substituted lower alkyl ester, a phenyl-lower alkyl ester or a phenacyl ester.
• the group Y1 or Y2 is a reactive residue, as the reactive residue, a substituted or non-substituted benzenesulfonyloxy group and a halogen atom may preferably be used.
• an alkali metal salt and an alkaline earth metal salt may be suitably used, and as salts of the amine compound (III) and the phenylalanine amide compound (V), an inorganic acid salt such as a mineral acid salt and an organic acid salt may be suitably used.
• the condensation reaction of the carboxylic acid compound (II) or a salt thereof and the amine compound (III) or a salt thereof may be carried out suitably in the presence of a dehydrating agent.
• a dehydrating agent any agent which can be used for synthesizing peptide may be used, and there may be mentioned, for example, water-soluble carbodiimide such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and dicyclohexylcarbodiimide.
• the condensation reaction of the reactive derivative in carboxyl group of the carboxylic acid compound (II) and the amine compound (III) or a salt thereof, and the condensation reaction of the indole compound (IV) and the phenylalanine amide compound (V) or a salt thereof may be carried out suitably in the presence or absence of an acid acceptor.
• an acid acceptor there may be used suitably any of an organic base such as tri-lower alkylamine, N,N-di-lower alkylamine or pyridine; and an inorganic base such as an alkali metal hydroxide, an alkali metal hydrogen carbonate, an alkali metal carbonate or an alkali metal hydride.
• the reactive derivative in carboxyl group of the carboxylic acid compound (II) there may be used those conventionally used in synthesizing peptide, for example, any of an acyl halide, an active ester, mixed acid anhydride and azide.
• reaction are preferably carried out in the presence of an appropriate solvent such as dimethylformamide, hexamethylphosphoric triamide, tetrahydrofuran, dioxane, acetonitrile or a mixed solvent thereof or without solvent under cooling to room temperature, preferably at -30 to 30 °C.
• an appropriate solvent such as dimethylformamide, hexamethylphosphoric triamide, tetrahydrofuran, dioxane, acetonitrile or a mixed solvent thereof or without solvent under cooling to room temperature, preferably at -30 to 30 °C.
• the protective groups R1 and/or R2 can be removed according to an ordinary method such as catalytic hydrogenolysis and acidic hydrolysis, depending on the kind of the protective group. If required, the resultant compound can further be converted to an ester thereof or a pharmaceutically acceptable salt thereof according to an ordinary method.
• the starting compounds (II), (III) and (V) in the present invention are novel compounds.
• the carboxylic acid compound (II) can be prepared by reacting the indole compound (IV) wherein Y1 is amino group, with an aminoacetic acid compound represented by the formula (VI): wherein Y3 represents a reactive residue; and Z1 represents a protective group for the carboxyl group, in the presence of an acid acceptor and then removing the protective group Z1.
• the amine compound (III) in which X is oxygen atom can be prepared by reacting, for example, an aminopropionic acid compound represented by the formula (VII): Z2-NH-(CH2)2-COOH (VII) wherein Z2 represents a protective group for the amino group, with an isocyanoacetic acid compound represented by the formula (VIII): CN-CH2-COOR2 (VIII) wherein R2 has the same meaning as above, in the presence of an acid acceptor and then removing the protective group Z2.
• an aminopropionic acid compound represented by the formula (VII): Z2-NH-(CH2)2-COOH (VII) wherein Z2 represents a protective group for the amino group with an isocyanoacetic acid compound represented by the formula (VIII): CN-CH2-COOR2 (VIII) wherein R2 has the same meaning as above, in the presence of an acid acceptor and then removing the protective group Z2.
• the amine compound (III) in which X is sulfur atom can be prepared by subjecting the amine compound (III) wherein X is oxygen atom to ring opening reaction and treating the resulting compound with a sulfurizer such as 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide.
• a sulfurizer such as 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide.
• the phenylalanine amide compound (V) can be prepared by subjecting a phenylpropionic acid compound represented by the formula (IX): wherein Z3 represents hydroxyl group or a protected amino group, or a reactive derivative in the carboxyl group, and the amine compound (III) to condensation-reaction according to an ordinary method, and then, by converting Z3 to a reactive residue by, for example, tosylation when Z3 is hydroxyl group, or removing the protective group when Z3 is a protected amino group.
• a phenylpropionic acid compound represented by the formula (IX): wherein Z3 represents hydroxyl group or a protected amino group, or a reactive derivative in the carboxyl group, and the amine compound (III) to condensation-reaction according to an ordinary method, and then, by converting Z3 to a reactive residue by, for example, tosylation when Z3 is hydroxyl group, or removing the protective group when Z3 is a protected amino group.
• the indole-containing peptide (I) which is the desired compound of the present invention, an ester thereof and a pharmaceutically acceptable salt thereof have excellent neutral metalloendopeptidase inhibitory activity, and exhibit excellent diuretic and vasodilating activities and inhibitory activity on renin and aldosterone secretion based on inhibiting effect of atrial natriuretic peptide (ANP) degradation.
• APN atrial natriuretic peptide
• angiotensin-converting enzyme inhibiting agents such as captopril and derapril hydrochloride have been clinically used at present.
• ACE inhibiting agents such as captopril and derapril hydrochloride
• the desired product of the present invention, an ester thereof and pharmaceutically acceptable salts thereof have excellent characteristic that they have effects also on low renin hypertension while these ACE inhibiting agents have relatively small effects thereon.
• a mixture comprising 535 mg of the product prepared in Example 11, 4-ethoxycarbonyl-5- ⁇ 2-[N-((1S)-1-carboxy-2-(3-indolyl)ethyl)-(L)-phenylalanyl]aminoethyl ⁇ thiazole, 1.5 ml of 2 N sodium hydroxide solution and 2 ml of methanol was stirred for 2 hours under ice-cooling. After the solvent was removed by evaporation, 1.5 ml of 2 N hydrochloric acid solution was added to the residue.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Molecular Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Biophysics (AREA)
• General Health & Medical Sciences (AREA)
• Genetics & Genomics (AREA)
• Medicinal Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Biochemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Crystallography & Structural Chemistry (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Indole Compounds (AREA)

Priority Applications (4)

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Cited By (6)

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• 1992
  • 1992-12-28 JP JP4349276A patent/JPH06199850A/ja active Pending
• 1994
  • 1994-06-22 US US08/264,061 patent/US5523313A/en not_active Expired - Fee Related
  • 1994-06-24 CA CA002126702A patent/CA2126702A1/en not_active Abandoned
  • 1994-06-27 EP EP94304653A patent/EP0690070A1/de not_active Withdrawn

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